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  • br The AHR functions in the

    2024-04-01


    The AHR functions in the immune system – a tsunami of exciting findings The research of recent years has convincingly established an important function of the AHR in linking chemical environmental cues to immune responses [21,22], and reviewed in [1,23]. As a side effect, a view of the AHR as “The Dioxin Receptor” became quite simply obsolete. Man-made chemical pollutants such as dioxins, furans and many other PAH are AHR-ligands. Indeed, the toxicity of PHAH/PAH may have shaped evolution of the human AHR after hominins began to use fire [24]. Today, these compounds continue to shape our gut microbiome [25]. Beyond man-made PAHs also many natural sources of AHR-ligands (agonists and antagonists) exist. UVB-radiation and sun light generate the high affinity ligand 6-formylindolo [3,2-b]carbazole (FICZ) [26,27]; bacteria and fungi on the skin and in the gut produce various AHR-binding indoles, phenazines or even highly complex molecules such as malassezin [28–31]. Quantitatively significant amounts of AHR-ligands are found in cruciferous dietary plants. Last but not least, kynurenines, products of intracellular tryptophan breakdown, are endogenous AHR ligands, albeit comparatively weak ones [29,32]. Notably, exposure to all these chemicals is via the barrier tissues, which are guarded and protected by their associated immune cells. Intriguingly, chloracne has not been observed for any of these natural agonists. As it turned out, AHR is involved in many aspects of the development and function of the immune system [33–36]. For instance, using full and conditional AHR-deficient mice, it was established that AHR signaling is required for the proper development of the ILC3 immune sphingosine in the gut [13,37], and for variant and invariant, mucosal tissue-specific γδ T cells [14,38,39]. Indeed, some γδ T cells actively regulate their uptake of tryptophan by CD69/LAT surface expression, eventually increasing intracellular AHR-ligand levels and thereby IL22 secretion [40]. One immune function of AHR-signaling in particular has drawn the attention of many laboratories: the role of AHR in the control of inflammatory versus regulatory helper T cells (Treg) and cytotoxic T cells [41]. This is so important because it may underlie a novel therapeutic potential in devastating autoimmune diseases such as multiple sclerosis, colitis, arthritis and others [42–46]. AHR is a transcription factor decisive for optimal differentiation of Th17 cells [47] and, in particular, their IL22 production [21,29]. Th17 cells are pivotal for the anti-bacterial immune response, but also exacerbate autoimmune diseases such as multiple sclerosis or psoriasis [48]. IL22 participates in many chronic inflammatory conditions, including in the skin. It promotes keratinocyte hyperplasia and epidermal remodeling in 3D-cultures, and has been suggested as a target in the treatment of psoriasis [49]. Various subsets of regulatory T cells such as FoxP3+ Treg or Tr1 cells, are also responsive to AHR signaling, either directly or indirectly via tolerogenic dendritic cells (DC) [45,50–53]. Moreover, AHR signaling controls a battery of barrier genes in the skin [15,54,55], and is therefore also involved in the non-immunological skin barrier. Thus, filaggrin (a major keratinocyte protein) is a direct target of AHR, and keratins or small proline-rich proteins (which code for precursor proteins of the cornified envelope, i.e. the outermost epidermal barrier) are modulated in stressed AHR-deficient epidermis, whether directly or indirectly is not clear yet [15,54].
    Tryptophan metabolism and inflammatory skin disease T cells need the amino acid tryptophan (Trp) for proliferation. Immunosuppression can be achieved by metabolic depletion of Trp. Findings that the Trp metabolizing enzymes indole-2,3-dioxygenase (IDO) induction is impaired in AHR-deficient DC [56,57] triggered the idea that the AHR acts immunosuppressively by influencing the regulation of IDO, and in some cell types also tryptophan hydroxylase (TDO) [57,58]. IDO is produced by many cell types, including immune cells and mesenchymal stem cells, and of great interest in questions of immune evasion of cancers.